Objective: GM3 synthase deficiency has been rarely reported to cause dystonia. We report three cases of affected siblings involving a prominent dystonic phenotype.

Background: Gangliosides are glycosphingolipids with sialic acid residues that are richly expressed within the nervous system. Their expression in neuronal cell membranes has roles in neuronal differentiation and cell regulation during brain development(1). The ST3GAL5 gene encodes the enzyme GM3 synthase, and its deficiency causes a rare condition which is described to cause refractory epilepsy, profound intellectual disability, hearing and vision loss, quadriplegia, choreoathetosis, as well as pigmentary skin changes(2-4).

Method: We report three siblings affected by GM3 synthase deficiency.

Results: The three reported Amish siblings were born of unaffected consanguineous parents. One other sibling who is deceased, and two other relatives are affected and not reported here. The three affected siblings were confirmed to have GM3 synthase deficiency. They all developed refractory epilepsy and developmental regression within the first few months of life. They are currently bedbound and have high-arched palates as well as musculoskeletal abnormalities. Cognitively they are nonverbal, and do not visually track. Patient 1: A 34 year old female who exhibits frequent repetitive puckering movements of her lips, as well as jaw closure dystonia with audible bruxism. There is prominent dynamic retrocollis and left torticollis. There are semi-stereotyped proximal left arm ballistic movements. There is diffuse hyperreflexia with hypotonia of the upper limbs and hypertonia of the right greater than left leg. Patient 2: A 33 year old male who exhibits possible mild dystonia, with hypertrophy of bilateral sternocleidomastoid muscles, although the head rests in neutral position. There is hyperreflexia and spasticity in the lower extremities. Patient 3: A 23 year old male with dynamic and moderate retrocollis. There are spontaneous writhing, non-purposeful movements of all limbs, as well as twisting dystonic movements involving wrist extension bilaterally. He is diffusely spastic.

Conclusion: We report three Amish siblings with GM3 synthase deficiency, two of whom developed prominent dystonic features during adulthood. To our knowledge, there is only one other individual who has been reported to have dystonia due to GM3 synthase deficiency(2).

References: 1. Yu RK, Nakatani Y, Yanagisawa M. The role of glycosphingolipid metabolism in the developing brain. J Lipid Res. 2009;50 Suppl(Suppl):S440-5. Epub 2008/10/11. doi: 10.1194/jlr.R800028-JLR200. PubMed PMID: 18845618; PubMed Central PMCID: PMCPMC2674698. 2. Gordon-Lipkin E, Cohen JS, Srivastava S, Soares BP, Levey E, Fatemi A. ST3GAL5-Related Disorders: A Deficiency in Ganglioside Metabolism and a Genetic Cause of Intellectual Disability and Choreoathetosis. J Child Neurol. 2018;33(13):825-31. Epub 2018/09/07. doi: 10.1177/0883073818791099. PubMed PMID: 30185102; PubMed Central PMCID: PMCPMC6188822. 3. Simpson MA, Cross H, Proukakis C, Priestman DA, Neville DC, Reinkensmeier G, et al. Infantile-onset symptomatic epilepsy syndrome caused by a homozygous loss-of-function mutation of GM3 synthase. Nat Genet. 2004;36(11):1225-9. Epub 2004/10/27. doi: 10.1038/ng1460. PubMed PMID: 15502825. 4. Fragaki K, Ait-El-Mkadem S, Chaussenot A, Gire C, Mengual R, Bonesso L, et al. Refractory epilepsy and mitochondrial dysfunction due to GM3 synthase deficiency. Eur J Hum Genet. 2013;21(5):528-34. Epub 2012/09/20. doi: 10.1038/ejhg.2012.202. PubMed PMID: 22990144; PubMed Central PMCID: PMCPMC3641379.

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